The three coenzymes biotin, tetrahydrofolate, and the
vitamin B12 derivative methylcobalamin (Fig. 7) act as
carriers of the single-carbon compounds CO2, bicarbonate
ions, formaldehyde, and formic acid. The combining of
biotin with CO2 is not a spontaneous process but depends
upon adenosine triphosphate (ATP), which serves as both
a phospho group carrier and the common energy currency
for many cellular reactions. It can also be regarded as a
coenzyme. In order to be activated by reaction with ATP,
the CO2 must first combine with a hydroxide ion to form
bicarbonate HCO3−. ATP then transfers a phospho group
to the bicarbonate, forming the labile and short-lived carboxyl
phosphate (−OOC—O—PO32−) together with adenosine
diphosphate (ADP). The carboxyl phosphate, in turn,
transfers the carboxyl group to the biotin prosthetic groups
of the various carboxylase proteins. From them the carboxyl
group is transferred onto the various sites marked by
arrows in Fig. 17. An inorganic phosphate ion is released
when the carboxyl group is transferred to biotin, completing
a sequence that couples activation of CO2 with the
cleavage of ATP to ADP and inorganic phosphate (Pi).
Such coupling of ATP cleavage to biosynthesis is a common
feature of much of biosynthetic metabolism.

Two other biotin-dependent reactions of great significance
are the carboxylation of acetyl-CoA to malonyl-
CoA and that of pyruvate to oxaloacetate (Fig. 17). The
former is essential to biosynthesis of fatty acids, which
are formed in a pathway which parallels (in reverse) that
of β oxidation (Fig. 12). However, there are several differences.
In the biosynthetic pathway, acetyl-CoA is first
converted to malonyl-CoA which undergoes decarboxylation
when a two-carbon unit is added to the growing fatty
acid chain. This decarboxylation, together with the prior
carboxylation steps, couples ATP cleavage to the biosynthesis.
Furthermore, NADPH is used in the reduction steps
rather than NADH or FADH2. In addition, the acyl carrier
is not coenzyme A but the related prosthetic group of acyl
carrier protein. Another biosynthetic process that depends
upon biotin is the synthesis of glucose in the liver. Pyruvate,
a product of glucose breakdown, is carboxylated to
oxaloacetate which is later decarboxylated on its pathway
to glucose. Again ATP cleavage is coupled to biosynthesis
with the help of biotin.

Tetrahydrofolates (THF) interconvert several onecarboncompounds
or fragments. As is indicated in Fig. 18,
formaldehyde released from the PLP-dependent cleavage
of serine is immediately trapped by THF (Fig. 14). Nitrogen
N1 adds to formaldehyde to form a carboxymethyl
(—CH2—COOH) derivative which can than react reversibly
with loss of water to form a cyclic adduct
(Fig. 18). This compound can be oxidized to the N10-
methyl form. Both of these are important intermediates
in a variety of biosynthetic processes. The third onecarbon
carrier is vitamin B12 which can act as an acceptor,
taking the methyl group from methyl-THF to form
methylcobalamin (Fig. 7). This compound is transferred
to the amino acid homocysteine to form methionine, one
of the 20 major amino acids from which proteins are constructed.
The reaction accounts for the second human requirement
for vitamin B12. If the methionine dietary intake
is high enough, this reaction is less important, but the enzyme
is still essential for remethylation of homocysteine
formed when methionine is used in a variety of processes
of biological methylation.

The double ring system on which folic acid (Fig. 6)
is constructed is known as pterin. In addition to the folates,
a number of other pterin coenzymes are found in
the human body and elsewhere in nature. Several have
shorter side chains at the 6-position on the ring. Some of
these compounds are used to color butterfly wings. Another,
called biopterin, has a three-carbon side chain that
carries two hydroxyl groups. Its reduced form, tetrahydrobiopterin,
is a
coenzyme for a series of hydroxylases.
Among these is phenylalanine hydroxylase which is lacking
in the well-known human genetic defect phenylketonuria
(PKU). The reduced pterin ring has properties similar
to those of FADH2. Molecular oxygen (O2) can add to
form a peroxide that can donate an OH group (formally as +OH) to convert phenylalanine to tyrosine. Phenylalanine
is toxic to the brain, accounting for the devastating symptoms
of PKU. Another pterin derivative is molybdopterin,
which has a four-carbon side chain containing two sulfur
atoms and an OH group. The human body, as well as all
other organisms, connects this OH group to a guanine
nucleotide to give a complex cofactor somewhat resembling
NAD+. The two sulfur atoms, however, bind to an
atom of the metal molybdenum. The molybdenum atom
is the site at which our bodies oxidize the toxic sulfite
(SO32−) to the harmless sulfate (SO42−). This coenzyme,
and the associated enzyme sulfite oxidase, are essential
to human life. Methane-forming bacteria create a different
complex side chain in methanopterin, which replaces
tetrahydrofolate in those organisms. Very complex pterin
derivatives form the red eye pigments of fruit flies.